Polymorphic regions and genes affecting gene transcription regulation of stress response and prolonged lifespan

Stress and cellular stress responses underlie many age-related diseases and understanding the causal link between the two is essential for promoting healthy aging strategies. There is accumulating evidence that exposure to a mild stressor induces an adaptive response that increases eukaryotic lifespan. Insight in the biological pathways associated with lifespan has been provided by, amongst others, transcriptome analysis. But so far it is unclear how natural genetic variation affects the complex transcriptional architecture which links stress response and lifespan. Here we report the detection of polymorphic regions in the genome (eQTL) and genes that regulate stress induced gene expression levels and prolong lifespan in the nematode C. elegans. Using 106 fully sequenced recombinant inbred lines (genetic mosaics and introgression lines) we found that heat-shock profoundly affected polymorphic distant gene expression regulators (distant-eQTL). A strong distant-eQTL affecting many transcripts was detected on the top left arm of chromosome IV. This eQTL coincided with a lifespan QTL and was validated by the gene expression profiles of introgression lines. Based on gene-network assisted candidate gene selection on the distant-eQTL, gene expression analysis of mutants carrying these candidate genes (cmk-1, egl-4, daf-11, eor-1 and unc-70) confirmed the eQTL. We found egl-4, and cmk-1 to be causally affecting gene expression patterns, stress resistance and prolonged lifespan. Our results show that natural variation affects stress response and lifespan by affecting thermo sensory circuits. This is the first study which unveils the transcriptional architecture and identifies genes linking stress response and lifespan based on natural genetic variation which opens up opportunities to genetically dissect age-related diseases.